Graduate School of Health Sciences, Sapporo Medical University, Sapporo, Japan.
School of Rehabilitation Sciences, Health Sciences University of Hokkaido, Tobetsu, Japan.
PLoS One. 2018 Jun 12;13(6):e0199050. doi: 10.1371/journal.pone.0199050. eCollection 2018.
Eccentric (ECC) contractions are used to maintain skeletal muscle mass and strength in healthy subjects and patients. Here we investigated the effects of ECC training induced by electrical stimulation (ES) on muscle wasting in colon 26 (C-26) tumor-bearing mice. Mice were divided into four groups: control (CNT), CNT + ECC, C-26, and C-26 + ECC. Cancer cachexia was induced by a subcutaneous injection of C-26 cells and developed for four weeks. In experiment 1, muscle protein synthesis rate and mammalian target of rapamycin complex (mTORC) 1 signaling were investigated six hours after one bout of ECC-ES (2 s contraction given every 6 s, 20°/s, 4 sets of 5 contractions). In experiment 2, ECC-ES training, a total of 14 sessions, was performed every other day starting one day after C-26 injection. Compared to the CNT mice, the gastrocnemius muscle weight was significantly decreased in the tumor-bearing mice. This change was accompanied by a reduction in protein synthesis rate and a marked increase in the expression levels of genes including regulated in development and DNA damage responses (REDD) 1, forkhead box protein O1 (FoxO1), muscle-specific E3 ubiquitin ligases atrogin-1, and muscle ring finger 1 (MuRF-1) mRNA. ECC-ES increased the protein synthesis rate and the phosphorylation levels of p70S6K (Thr389) and rpS6 (Ser240/244), markers for mTORC1 signaling, and reversed an upregulation of MuRF-1 mRNA in muscles from C-26 mice. Our findings suggest that ECC-ES training reduces skeletal muscle atrophy in C-26 tumor-bearing mice through activation of mTORC1 signaling and the inhibition of ubiquitin-proteasome pathway. Thus, ECC-ES training might be used to effectively ameliorate muscle wasting in patients with cancer cachexia.
离心（ECC）收缩用于维持健康受试者和患者的骨骼肌质量和力量。在这里，我们研究了电刺激（ES）引起的 ECC 训练对结肠 26（C-26）荷瘤小鼠肌肉减少症的影响。将小鼠分为四组：对照组（CNT）、CNT+ECC、C-26 和 C-26+ECC。通过皮下注射 C-26 细胞诱导癌症恶病质，并持续四周。在实验 1 中，在单次 ECC-ES 后 6 小时研究了肌肉蛋白质合成率和哺乳动物雷帕霉素靶蛋白复合物（mTORC）1 信号。在实验 2 中，在 C-26 注射后一天开始，每隔一天进行总共 14 次 ECC-ES 训练。与 CNT 小鼠相比，荷瘤小鼠的腓肠肌重量明显降低。这种变化伴随着蛋白质合成率的降低和包括调节发育和 DNA 损伤反应（REDD）1、叉头框蛋白 O1（FoxO1）、肌肉特异性 E3 泛素连接酶 atrogin-1 和肌肉环指蛋白 1（MuRF-1）mRNA 在内的基因表达水平的显著增加。ECC-ES 增加了蛋白质合成率和 mTORC1 信号标志物 p70S6K（Thr389）和 rpS6（Ser240/244）的磷酸化水平，并逆转了 C-26 小鼠肌肉中 MuRF-1mRNA 的上调。我们的研究结果表明，ECC-ES 训练通过激活 mTORC1 信号和抑制泛素蛋白酶体途径来减少 C-26 荷瘤小鼠的骨骼肌萎缩。因此，ECC-ES 训练可能用于有效改善癌症恶病质患者的肌肉减少症。
